This proposed Center will focus upon defects in gonadotropin synthesis, secretion, a/o action in the human. Project I will continue our exploration of the neuroendocrine control of the midcycle gonadotropin surge and luteal-follicular transition and thus provides a physiologic backdrop for the more therapeutic studies in the subsequent Projects. Project II attempts to build upon the known safety, efficacy, and cost- benefits of pulsatile GnRH treatment to induce ovulation by exploring its therapeutic role n women with hypothalamic amenorrhea (vs. exogenous gonadotropins), acquired hypogonadism, PCOS, and unexplained infertility. Project III focuses upon the male and examines the roles of i) the contour of the stimulatory pulse of GnRH; ii) the level and pattern of gonadal steroid feedback; and iii) inhibin in the differential control of gonadotropin secretion in normal and infertile men. It will also explore the utility of inhibin as a marker of spermatogenesis and the genetics of isolated gonadotropin deficiency using newly identified molecular probes to improve our understanding of the inheritance of reproductive function in the human. Project IV reinforces the clinical investigational inquiries of Project III with an in vitro perfusion system which permits parallel exploration of secretory and biosynthetic events. The transcriptional response elements and post-transcriptional regulation of gonadotropin mRNA by GnRH, inhibin, and activin will be investigated in this section. Project V employs recently developed radioreceptor assays to determine the frequency and assist with the isolation and characterization of circulating gonadotropin receptor antagonists in men and women with hypergonadotropic failure. The natural history of this disorder will be examined and the impact of gonadotropin suppression on it will be investigated. Project VI proposes to establish and validate new dimer- specific sandwich assays for measurement of inhibin and its subunits, to use these assays to support the other projects in defining its physiologic and pathologic role, and in exploring extragonadal sources of its production. All projects are highly interactive, mutually reinforcing, and constructed in such a fashion as to build upon recent advances in such a manner as to provide the swiftest possible transfer from basic science to clinical application in the field of infertility research.